The invention described herein was not made with the aid of any federally sponsored grants.
The field of the invention is in novel substituted pyrimidine compounds and their use as pharmacologically active agents capable of suppressing and inhibiting viruses (e.g., herpes viruses). The subject compounds and compositions are particularly useful in treating and suppressing human Cytomegalovirus.
Cytomegalovirus (CMV) is a member of the herpes virus family. Other well-known members of the herpes virus family include, for example, herpes simplex virus, types I and II, Epstein-Barr virus and varicella zoster virus. These viruses are related taxonomically, but each manifests in a clinically distinct manner. In the case of CMV, medical conditions arising from congenital infection include jaundice, respiratory distress and convulsive seizures which may result in mental retardation, neurologic disability or death. Infection in adults is frequently asymptomatic, but may manifest as mononucleosis, hepatitis, pneumonitis or retinitis, particularly in immunocompromised patients such as AIDS sufferers, chemotherapy patients, and organ transplant patients undergoing tissue rejection therapy.
A variety of drugs have been developed to treat herpes virus infections, including naturally occurring proteins and synthetic nucleoside analogs. For example, the natural anti-viral protein interferon has been used in the treatment of herpes virus infections, as have the nucleoside analogs cytosine-arabinoside, adenine-arabinoside, iodoxyuridine and acyclovir, which is presently the treatment of choice for herpes simplex type II infection.
Unfortunately, drugs such as acyclovir that have proven sufficiently effective to treat infection by certain herpes viruses are not sufficiently effective to treat CMV. Additionally, drugs currently used to treat CMV infection, such as 9-((1,3-dihydroxy-2-propoxy)methyl)guanidine (ganciclovir, DHPG) and phosphonoformic acid (foscarnet), lack the acceptable side effect and safety profiles of the drugs approved for treatment of other herpes viruses. Moreover, such drugs are ineffective to treat certain strains of CMV that have acquired drug resistance. Thus, despite advances in the development of anti-herpes virus drugs, there remains a need for therapeutic agents effective in treating CMV infection with an increased safety margin. The present invention provides such therapeutic agents in the form of surprisingly effective substituted pyrimidine compounds.
The present invention provides novel substituted pyrimidine compounds. The compounds have the general formula I: 
in which X represents xe2x80x94NR3R4, xe2x80x94OR3, xe2x80x94SR3, aryl, alkyl or arylalkyl. The letter Y represents a covalent bond, xe2x80x94N(R6)xe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94C(xe2x95x90O)xe2x80x94 or an alkylene group. R1 and R2 are independently selected from hydrogen, alkyl, xe2x80x94O-alkyl, xe2x80x94S-alkyl, aryl, arylalkyl, xe2x80x94O-aryl, xe2x80x94S-aryl, xe2x80x94NO2, xe2x80x94NR7R8, xe2x80x94C(O)R9, xe2x80x94CO2R10, xe2x80x94C(O)NR7R8 xe2x80x94N(R7)C(O)R9, xe2x80x94N(R7)CO2R11, xe2x80x94N(R9)C(O)NR7R8, xe2x80x94S(O)mNR7R8, xe2x80x94S(O)nR9, xe2x80x94CN, halogen, and xe2x80x94N(R7)S(O)mR11. The groups R3 and R4 are independently selected from hydrogen, alkyl, aryl or arylalkyl, or, when X is xe2x80x94NR3R4, R3 and R4 taken together with the nitrogen atom to which each is attached form a 5-, 6- or 7-membered aromatic or nonaromatic ring containing from one to three heteroatoms in the ring. R5 and R6 are independently hydrogen, alkyl, aryl or arylalkyl. R7 and R8 are each independently hydrogen, alkyl, aryl or arylalkyl, or, when attached to the same nitrogen atom can be combined with the nitrogen atom to form a 4-, 5-, 6-, 7- or 8-membered ring containing from one to three heteroatoms in the ring. R9 and R10 are independently selected from hydrogen, alkyl, aryl and arylalkyl. R11 is selected from alkyl, aryl and arylalkyl. The subscript m is an integer of from 1 to 2 and the subscript n is an integer of from 1 to 3.
In addition to the above descriptions of R1 to R11, the formula above is meant to represent a number of compounds in which a second ring is fused to the pyrimidine ring. For example, R1 can be joined to R2, R1 can be joined to R3, R3 can be joined to N3 (the nitrogen atom at the 3-position of the pyrimidine ring), R5 can be joined to N3, R5 can be joined to N1 (the nitrogen atom at the 1-position of the pyrimidine ring) or R2 can be joined to N1 to form a fused 5-, 6-, or 7-membered ring.
Finally, the compounds of the present invention will typically have a molecular weight of from about 150 to about 750. The compounds provided in the above formula are meant to include all pharmaceutically acceptable salts thereof.
The compounds of the present invention are useful in therapeutic as well as prophylactic and diagnostic applications. Still further, the compounds are useful in the development of additional therapeutic agents as standards in a variety of assay formats. Accordingly, the present invention provides compositions containing the above compounds and pharmaceutically acceptable excipients or diagnostically acceptable excipients. The invention further provides methods of inhibiting or suppressing certain viruses, and methods of treating individuals infected with such viruses, particularly CMV. In addition to treatments for existing conditions, the present invention also provides methods for prophylactic treatments to prevent the onset of viral infection in patients undergoing, for example, organ transplants.
Other objects, features and advantages of the present invention will become apparent to those skilled in the art from the following description and claims.